The candidate's overall objective is to obtain sufficient independence and accomplishment as a clinical and basic science investigator and develop an academic career in pediatric neurosurgery with a research focus on brain injury and neuroplasticity in the immature. The MCSDA will provide the opportunity to devote the majority of time to research to develop a strong foundation in basic science, clinical research and teaching in the area of traumatic brain injury in children in the early stages of career development. This application proposes a basic science project with clearly accomplishable aims important for the understanding of the pathologic response of the immature brain to traumatic injury and combines this project with an active clinical program of head injury in children. This proposal is unique since the study of TBI in immatures has been hampered by the lack of a model producing a diffuse cerebral injury. We modified the recently described, diffuse closed-head injury model of Marmarou et al. (53) and have begun to characterize this model of diffuse TBI in immature (17 d) rats (3,4). In this application, we propose to further characterize this diffuse TBI model in the immature rat using two clinically available outcome parameters, namely function (motor and cognitive) and cerebral blood flow (CBF) and we will then use hypothermia to determine its effect on these parameters after diffuse TBI. The specific aims of the proposal are: l) to characterize the motor and cognitive (spatial memory acquisition and retention) deficits produced in the acute and chronic phases after diffuse TBI (closed head injury weight-drop) in immature (17 d) rats; 2) to describe the acute and chronic changes in CBF (hyperemia vs ischemia) and CO2 vasoresponsivity after this injury; and 3) to determine if moderate hypothermia (32 +/- 0.5 degrees C) applied in the acute period after diffuse TBI will reduce the functional, CBF, and histologic disturbances acutely and chronically in immature rats. The aims will be accomplished by performing serial assessments of functional outcome (cognition and motor) and determining CBF using iodo[14C] antipyrine (14C-IAP) autoradiography. Perfusion magnetic resonance imaging, (pMRI), a noninvasive serial assessment of regional CBF will be validated to autoradiography and then CO2 vasoresponsivity will be tested using pMRl following hyperventilation. Lastly, we will utilize moderate hypothermia after injury in this experimental model of TBI in the immature rat to determine its effect on function, CBF, and histology. Characterization of the functional, cerebrovascular and histologic disturbances in this unique model of diffuse brain injury should yield the first clues as to the mechanism(s) of diffuse swelling in the immature. Also this proposal should facilitate the development and testing of targeted therapies for eventual use after severe TBI in infants and children and provide important pre-clinical data for the multi-center trial of hypothermia in children.